Search Results (277)

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger–satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut–brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies. Full article

Severe skin injury in humans typically heals through fibrotic remodelling rather than true regeneration, resulting in permanent loss of appendages, sensory function, and tissue architecture. Over the past decades, advances in bulk, single-cell, and spatial transcriptomic profiling have revealed that cutaneous wound repair is governed by dynamic, context-dependent gene-regulatory programmes across epidermal, dermal, vascular, and immune compartments. These studies highlight substantial heterogeneity in keratinocyte, fibroblast, and immune cell states, and identify RNA-mediated regulatory networks that bias healing toward either regenerative or fibrotic outcomes. In parallel, stem cell-derived skin organoids and advanced engineered skin equivalents have emerged as experimental platforms capable of reproducing key aspects of human skin organisation, offering new opportunities to move beyond purely reparative grafting strategies. This review integrates evidence from human or murine skin and wound transcriptomics, RNA-based regulatory mechanisms, and organoid-based skin engineering relevant to trauma and burn reconstruction. We summarise how protein-coding and non-coding RNAs (including miRNAs and lncRNAs) coordinate epithelial migration, inflammation resolution, angiogenesis, and ECM remodelling, and how the dysregulation of these networks contributes to pathological scarring. This article synthesises transcriptomic, RNA regulatory, and skin organoid research to propose a conceptual, hypothesis-generating framework for regenerative skin repair, without claiming clinical readiness or validated therapeutic translation. Full article

Background and Objectives: The inner ear has traditionally been regarded as an immunoprivileged and anatomically isolated organ. However, growing interest in neuro-lymphatic interactions has raised the hypothesis that glymphatic and lymphatic mechanisms may contribute to auditory pathology and its association with cognitive dysfunction. This systematic review aimed to synthesize current human evidence regarding anatomical, imaging, and clinical correlates of glymphatic mechanisms in the inner ear and audiological pathologies, and to quantitatively evaluate currently available biomarkers. Materials and Methods: A structured search of PubMed, Scopus, and Cochrane databases was performed from inception through March 2026. Eligible studies included human investigations reporting anatomical, histopathological, or MRI-based glymphatic assessments related to inner ear disorders. Risk of bias was assessed using the Newcastle–Ottawa Scale and Joanna Briggs Institute tools. Meta-analysis was conducted for diffusion tensor image analysis along the perivascular space (DTI-ALPS) indices comparing auditory disorders with healthy controls. Results: Six studies met inclusion criteria (five cross-sectional imaging studies and one surgical histopathological case series). Histopathology demonstrated lymphatic capillaries in advanced Ménière disease. MRI studies consistently reported reduced ALPS indices and/or increased choroid plexus volume and enlarged perivascular spaces in tinnitus, congenital sensorineural hearing loss, and age-related hearing loss. Meta-analysis of five studies showed a significant reduction of ALPS index in auditory disorders compared with controls (SMD = −0.73, 95% CI −0.90 to −0.55; p < 0.001), with no heterogeneity. Glymphatic markers were frequently associated with audiological data, cognitive performance and inflammatory biomarkers. Conclusions: Human evidence supports the presence of altered central glymphatic function across diverse auditory phenotypes. Although predominantly based on indirect MRI proxies and cross-sectional data, the meta-analytic findings strengthen the biological plausibility of an auditory–glymphatic interaction. Prospective longitudinal studies are warranted to clarify causality and therapeutic implications. Full article

This review explores the hypothesis that schizophrenic symptoms may be understood not as isolated deficits, but as interconnected manifestations of a structural reorganization of consciousness. The premises of this work are grounded in a comparative matrix that suggests an underlying “consanguinity” between the philosopher’s voluntary epoché—the suspension of the natural attitude performed to study the inner workings of consciousness—and the involuntary “unworlding” passively experienced in schizophrenia. By exploring this shared ontological ground, the text suggests how specific phenomenological shifts, such as the collapse of the “vital drive,” may manifest as clinical markers; this process may eventually lead to an involuntary “transcendental reduction” where the mind’s internal machinery becomes an object of forced awareness. Building on these premises, the review tentatively outlines several key achievements. It addresses the substrate-subjectivity gap by linking biological sensory-binding failures to the onset of involuntary hyper-reflexivity. Regarding structural loss and gain of function, it suggests that the psychotic transition involves a simultaneous erosion of common-sense coherence and an intensified receptivity to unfiltered perceptual fragments, which may trigger a search for metaphysical meanings. In terms of a therapeutic synthesis, it proposes exploring the conversion of “artless decentering” into a manageable, strategic distance through mindfulness and person-centered position-taking. Finally, it discusses a potential nosographic evolution, advocating for future diagnostic classifications that prioritize the experiencing self and qualitative insights to support a more translational and empathetic approach to psychiatry. Full article

Financial time series in turbulent markets exhibit complex long-memory dynamics and multifractal features that traditional deep learning models fail to capture due to inherent exponential forgetting mechanisms. To address this, we propose Frac-Attn-GL, a novel Fractional-order Spatiotemporal Attention-based GRU-LSTM framework. Grounded in the Fractal Market Hypothesis, the model embeds Grünwald–Letnikov fractional-order operators into a dual-channel architecture (FracLSTM and FracGRU) to characterize long-range memory with rigorous power-law decay priors. Furthermore, an extreme-aware asymmetric loss function is designed to drive a dynamic spatiotemporal routing mechanism, enabling adaptive shifts between long-term macro trends and short-term micro shocks. Empirical tests on major U.S. stock indices reveal three significant findings. First, the Frac-Attn-GL framework substantially reduces prediction errors, achieving up to a 93.1% RMSE reduction on the highly volatile NASDAQ index compared to standard baselines. Second, the adaptively learned fractional-order parameters exhibit a consistent quantitative alignment with the market’s empirical multifractal singularity spectrum, supporting the physical interpretability of the model’s endogenous memory mechanism. Finally, hybrid residual multifractal diagnostics indicate that the framework effectively captures deep long-range correlations, reducing the Hurst exponent of the prediction residuals from ~0.83 to approximately 0.50, a level consistent with the absence of significant long-range dependence. Full article

Background/Objectives It is known that failure to gain sufficient bone during skeletal growth and maturation phases predisposes to the development of senile osteoporosis as age-related bone loss ensues. There is limited knowledge about factors that are necessary for the pubertal growth spurt and achievement of peak bone mass. Diminution or disappearance of Juvenile Protective Factors (JPFs) after a given maturational stage could contribute to the onset of age-related declines in a variety of physiological functions, including bone physiology. Methods With available pediatric platelet-poor plasma (PPP) and mesenchymal/skeletal stem cells (MSCs), we tested whether proteomics and RNA-seq methodology have potential for the discovery of novel regulators of pubertal skeletal growth. Results Our data demonstrate that pediatric PPP rejuvenates age-related compromised MSC functions; that Mass Spectrometry (MS)-based proteomics identified known and novel circulating tissue growth/trophic factors in human PPP of pubertal, as compared with pre-pubertal, and post-pubertal subjects; and that the unbiased RNA-Seq approach revealed new genes and networks of genes that are dramatically elevated or diminished in pubertal MSCs. Conclusions The findings support the hypothesis that the characterization of pro-osteogenic JPFs could lead to the identification of novel therapeutic approaches to promote bone health in the elderly and of potential treatment regimens for senile osteoporosis. Full article

K-Rev Interaction Trapped protein-1 (KRIT1) is a scaffold protein that forms functional protein complexes involved in physiologically important signaling networks. While it is primarily recognized for its association with Cerebral Cavernous Malformations (CCMs), KRIT1 may also play critical roles in tumor formation and the acquisition of malignant phenotypes, regulating cell adhesion, cytoskeletal dynamics, and angiogenesis. In this study, we investigated the role of KRIT1 in cancer cell migration and metastasis, with a focus on identifying novel interacting proteins and characterizing the intracellular signaling pathways activated upon its loss. By using a yeast two-hybrid screening, we identified Kinesin Family Member 1C (KIF1C), a protein involved in regulating podosome and invadopodium elongation, as a novel binding partner of KRIT1, and the interaction was confirmed in melanoma and epithelial cancer cells. In silico docking and interaction interface analyses supported the KRIT1–KIF1C interaction, providing structural insight into the binding mode as shown experimentally. We also found that SRC and focal adhesion kinase (FAK) phosphorylation, as well as Ras homolog family member A (RhoA) expression, represent additional pathways affected by the loss of KRIT1. This study confirms our earlier hypothesis that KRIT1 functions as a tumor suppressor and uncovers a compelling link between its loss and enhanced cancer aggressiveness. Full article

Background and objectives: Early recovery after major head-and-neck reconstruction is shaped by nutritional vulnerability and functional decline. We evaluated whether preoperative CT-defined low skeletal muscle mass—considered here as an imaging-derived muscle-depletion phenotype rather than the full consensus syndrome of sarcopenia—predicts swallowing milestones, weight trajectory, and patient-reported outcomes at 12 weeks. Methods: In a prospective longitudinal cohort of 74 adults undergoing oncologic resection with reconstruction, low skeletal muscle mass was derived from preoperative cervical CT-based skeletal muscle measurements and nutritional risk was screened with NRS-2002. Outcomes included FOIS, PEG dependence, percent weight loss, MDADI, and European Organisation for Research and Treatment of Cancer QLQ-C30/QLQ-H&N35 at 12 weeks. A multivariable logistic regression explored a composite poor-recovery endpoint (PEG at 12 weeks and/or FOIS ≤ 3 and/or MDADI < 55). Results: Low skeletal muscle mass (32/74, 43.2%) was associated with longer length of stay (13.4 ± 4.1 vs. 10.3 ± 3.3 days; p < 0.001) and more major complications (31.2% vs. 11.9%; p = 0.04). At 12 weeks, affected patients had greater weight loss (10.9 ± 3.4% vs. 8.6 ± 2.6%; p = 0.003), lower FOIS (3.9 ± 1.1 vs. 4.6 ± 1.1; p = 0.01), lower MDADI (57.1 ± 10.9 vs. 66.6 ± 11.9; p = 0.001), and higher PEG dependence (31.2% vs. 9.5%; p = 0.018). Low skeletal muscle mass remained associated with poor recovery after adjustment (aOR 5.4; 95% CI 1.4–24.0; p = 0.016); adjuvant radiotherapy was also associated (aOR 4.3; p = 0.049). Model discrimination was good (AUC 0.81). Conclusions: Preoperative CT-defined low skeletal muscle mass was associated with impaired early recovery after major head-and-neck reconstruction, particularly when adjuvant radiotherapy was anticipated; however, these findings should be interpreted as exploratory and hypothesis-generating. Full article

In classical reliability engineering, failure is a probabilistic structural failure based on lifetime distributions of Weibull models. However, in the control-critical mechanical systems, it is possible that functional failure of the system happens before material failure occurs as a result of control power loss. This paper proposes a Controllability–Reliability Coupling (CRC) model, which redefines the concept of reliability as the stabilizability in the face of progressive degradation. The actuators’ deterioration is modeled using the time-varying input effectiveness factor $\alpha \left(t\right)$, and the actuator is said to be in failure when the minimum singular value of the finite-horizon controllability Gramian becomes less than a stabilizability threshold $\epsilon$. The performance of the simulation indicates that the functional failure is a precursor of structural failure in several degradation conditions. A baseline comparison shows that the CRC metric forecasts loss of controllability at $T_{CRC}=17.0$ s, but the classical Weibull reliability never attains the structural failure threshold even in the time horizon of 20 s. The system retains margins of Lyapunov stability and H infinity robustness are not lost, and it is still stable and attenuates disturbances even when control authority is lost. In practical degradation scenarios, the forecasted CRC failure times are 21.5 s (linear wear), 13.1 s (accelerated fatigue), 23.7 s (intermittent faults), and 24.4 s (shock damage), whereas maintenance recovery abated functional failure completely. In a case study of an industrial robotic joint, at 27.0 s, functional collapse occurred, and at the same time, structural reliability was still above the failure threshold. The findings support the hypothesis that structural survival and functional controllability are distinct concepts. The proposed CRC framework is an approach to control-conscious reliability measure, which can detect early failures and offer proactive maintenance advice in the context of a cyber–physical system. Full article

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect. Full article

Space-based multi-target passive tracking is critical for space situational awareness, but faces severe challenges due to the limited field-of-view (FoV) and directional ambiguity of onboard sensors. These constraints often lead to target loss, poor observability, and decreased estimation accuracy. To address these issues, different fusion architectures have been explored. While centralized measurement-level fusion offers superior accuracy for estimating target states, distributed estimation-level fusion provides greater reliability for estimating the number of targets. To adaptively leverage these two complementary strengths, a dynamic hierarchical fusion method through real-time optimization of the fusion topology is proposed. Specifically, at each decision epoch, sensor nodes are dynamically partitioned into local fusion nodes (LFNs) and detection-only nodes (DONs). Each LFN receives measurements from selected DONs and executes an iterated-correction Gaussian-mixture probability hypothesis density filter. Subsequently, LFNs share and fuse their estimates using the intensity-dependent arithmetic average fusion. This dynamic process is achieved by applying a sensor management scheme based on partially observable Markov decision process (POMDP). To ensure accurate cardinality estimation, the reward function in POMDP utilizes the posterior expected number of targets. The resultant optimization is efficiently solved using a binary particle swarm optimization algorithm. Numerical and hardware-in-the-loop simulations demonstrate the effectiveness of the proposed method in balancing the accuracy of target number and state estimation. Full article

The loss of estrogen following menopause is associated with a marked increase in cardiometabolic risk, accompanied by adverse changes in lipid metabolism, insulin sensitivity, vascular function, and systemic inflammatory tone. Emerging evidence suggests that estrogen signaling interacts with chromatin regulatory mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, across multiple metabolic tissues. In this review, we examine current evidence linking estrogen receptor signaling to epigenetic modulation in cardiovascular, hepatic, adipose, vascular, and immune systems. We propose that epigenetic remodeling represents a plausible and testable mechanistic framework connecting estrogen depletion to cardiometabolic disease progression, while acknowledging that much of the mechanistic evidence derives from preclinical and in vitro systems and that direct longitudinal validation in human cardiovascular tissues remains limited. We further explore how this framework may contribute to understanding the “estrogen paradox” and the heterogeneous outcomes of hormone replacement therapy (HRT), particularly within the context of the timing hypothesis. Finally, we evaluate pharmacologic and lifestyle interventions, including structured exercise, dietary modulation, and cardiometabolic therapeutics, through the lens of potential epigenetic influence. Clarifying tissue-specific and immune-integrated chromatin responses to estrogen loss will be essential for advancing precision strategies aimed at improving cardiometabolic health in postmenopausal women. Full article

Background: Spinal cord injury (SCI) is a leading cause of chronic disability. Loss of upper extremity (U.E.) function is central to limitations, in mobility, postural control, transfers, and self-care. The aim of this exploratory pilot study was to investigate whether self-reported UE function is associated with independence in activities of daily living (ADLs) in people with motor-incomplete tetraplegia. Methods: Eleven (n = 11) individuals with motor-incomplete tetraplegia (AIS C–D; neurological levels C4–T1; injury duration ≥ 1 year), recruited through convenience sampling from five specialist rehabilitation centres, participated in an exploratory cross-sectional pilot study designed to generate hypotheses rather than test them. U.E. function was assessed using the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire, selected for its ability to capture pain and task-related functional difficulty in the elbow, wrist, and hand; its application in this neurological population is considered exploratory. Independence in ADLs was evaluated using the Spinal Cord Independence Measure III (SCIM III). Given the small sample, all analyses were primarily descriptive and along with bivariate associations (Spearman correlations). Regression findings are reported strictly for exploratory purposes. Results: The median age was 50 years (interquartile range [IQR] 43–55). A strong negative correlation was observed between PRTEE total score and SCIM III (r_s = −0.76). In an exploratory univariate analysis, each 1-point increase in PRTEE total score was associated with a 1.3-point lower SCIM III score (β = −1.3, 95% CI −2.34 to −0.26, p = 0.02). Age also showed a positive association (β = 1.31, 95% CI 0.04 to 2.58, p = 0.05) with SCIM III; however, this finding is highly likely to reflect a statistical artefact of the small and unrepresentative sample. Multivariable regression was not conducted as a primary analysis due to insufficient statistical power. All findings should be treated as strictly exploratory and hypothesis-generating. Conclusions: Self-reported U.E. function appears to be associated with ADL independence in motor-incomplete tetraplegia. U.E. capacity may contribute to functional tasks requiring postural stability and mobility-related activities, but no predictive inferences can be made from this underpowered, convenience sample. Future studies with larger cohorts and performance-based measures are needed to confirm these preliminary observations and clarify the role of U.E. function in rehabilitation planning. Full article

Long-term stability of multienzyme protein systems is governed by preservation of conformational integrity and resistance to thermally induced structural destabilization. This study evaluated bovine pancreatin (BP) obtained by conventional extraction (CM) and ultrasound-assisted extraction (UAM) during 0–930 days of storage at 10–40 °C. Amylolytic (AA), proteolytic (PA), and lipolytic activities (LA), representing the functional enzymatic activity (EA) of the multienzyme protein system, were monitored to characterize degradation kinetics and activity loss associated with conformational destabilization. After 930 days at 20 ± 1 °C, UAM retained 76% of initial AA compared with 58% for CM, corresponding to a 31% higher residual activity in UAM. LA demonstrated comparatively high stability in both preparations (~84% retention), whereas PA exhibited delayed degradation and significantly higher residual values in UAM samples. Two-way ANOVA confirmed significant effects of extraction method, storage duration, and their interaction (p < 0.001), indicating method-dependent kinetic behavior. Elevated temperatures (35–40 °C) accelerated inactivation, consistent with increased molecular mobility and reduced conformational stability. The smoother degradation trajectories and lower apparent inactivation rates observed in UAM preparations suggest kinetic stabilization, potentially associated with improved conformational preservation and reduced extraction-induced structural stress. Both preparations complied with pharmacopoeial microbiological limits. These findings support the hypothesis that UAM enhances long-term functional stability of complex multienzyme systems through mechanisms related to conformational resilience. Full article

Background/Objectives: Long COVID has emerged as a significant public health concern, characterized by persistent symptoms following SARS-CoV-2 infection. Cognitive impairment is a common sequela, particularly among older adults (OAs). Although olfactory dysfunction and malnutrition have been previously associated with cognitive decline, it remains elusive to what extent sex-specific variations in these and additional factors will be pivotal to guiding targeted interventions in a sex-specific manner. To fill this gap in knowledge, we undertook a study with the purpose of investigating the contribution of sex-specific risk factors to the development of cognitive impairment (CI) in a cohort of OAs hospitalized with long COVID. Methods: We undertook a cross-sectional study among OAs hospitalized at a geriatric care unit. Olfactory function was assessed using the Sniffin’ Stick Test. Cognitive impairment was evaluated by the Mini-Mental State Examination, and nutritional status was assessed with the Mini Nutritional Assessment (MNA). Statistical analyses included linear regression. Results: A total of 45 patients with long COVID were included, of whom 51% were female. The prevalence of CI was lower in men compared to women. In the single variable analysis, nutritional factors were associated with CI only in women; importantly, the loss of olfactory function was associated with CI in the whole group and to CI in women after multivariate analysis. Conclusions: Olfactory dysfunction is a potential biomarker for cognitive impairment in OAs with long COVID in a sex-specific manner. In our study nutritional status and probable obesity could be additional factors associated with CI; nevertheless, this was not confirmed in our multivariate analysis; therefore, this hypothesis would need to be tested in larger studies. Full article